Exploiting bacterial DNA gyrase as a drug target: current state and perspectives.
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TLDR
Known gyrase-specific drugs and toxins are reviewed and the prospects for developing new antibacterials targeted to this enzyme are assessed.Abstract:
DNA gyrase is a type II topoisomerase that can introduce negative supercoils into DNA at the expense of ATP hydrolysis. It is essential in all bacteria but absent from higher eukaryotes, making it an attractive target for antibacterials. The fluoroquinolones are examples of very successful gyrase-targeted drugs, but the rise in bacterial resistance to these agents means that we not only need to seek new compounds, but also new modes of inhibition of this enzyme. We review known gyrase-specific drugs and toxins and assess the prospects for developing new antibacterials targeted to this enzyme.read more
Citations
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Structure-based discovery of substituted 4,5'-bithiazoles as novel DNA gyrase inhibitors.
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YcaO-Dependent Posttranslational Amide Activation: Biosynthesis, Structure, and Function
Brandon J. Burkhart,Christopher J. Schwalen,Greg Mann,James H. Naismith,James H. Naismith,Douglas A. Mitchell +5 more
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References
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The aminocoumarins: biosynthesis and biology
TL;DR: The biosynthetic gene clusters of all five aminocoumarin antibiotics have been identified, and the gene functions have been studied by genetic and biochemical methods and are now one of the best-understood pathways of secondary metabolism in streptomycetes.
Journal ArticleDOI
Active-Site Residues of Escherichia coli DNA Gyrase Required in Coupling ATP Hydrolysis to DNA Supercoiling and Amino Acid Substitutions Leading to Novobiocin Resistance
Christian H. Gross,Jonathan D. Parsons,Trudy H. Grossman,Paul S. Charifson,Steven Bellon,James Jernee,Maureen D. Dwyer,Stephen P. Chambers,William Markland,Martyn Botfield,Scott A. Raybuck +10 more
TL;DR: Interestingly, GyrB proteins with P79A and K103A substitutions retained significant levels of ATPase activity yet demonstrated no DNA supercoiling activity, even with 40-fold more enzyme than the wild-type enzyme, suggesting that these amino acid side chains have a role in the coupling of the two activities.
Journal ArticleDOI
Cloning and analysis of the simocyclinone biosynthetic gene cluster of Streptomyces antibioticus Tü 6040.
TL;DR: Experimental proof for the function of the identified gene cluster was provided by a gene inactivation experiment, which resulted in the abolishment of the formation of the aminocoumarin moiety of simocyclinone.
Journal ArticleDOI
The interaction of drugs with DNA gyrase: a model for the molecular basis of quinolone action.
TL;DR: A model for the gyrase-quinolone-DNA complex is proposed, which suggests that the drugs thought to act by stabilising a cleavage complex between gyrases and DNA that arrests polymerases in vivo are coumarin and quinolone drugs.
Journal ArticleDOI
Evidence for a conformational change in the DNA gyrase–DNA complex from hydroxyl radical footprinting
TL;DR: Gyrase protects 128 bp from the hydroxyl radical with the central 13 bp (adjacent to the gyrase cleavage site) being most strongly protected, suggesting a helical repeat of 10.6 bp consistent with the DNA being wrapped upon the enzyme surface.
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